Trial Review

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A randomised controlled trial of bisphosphonate therapy in osteonecrosis of the hip.

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Scientific title

A randomised controlled trial to study the effectiveness of potent bisphosphonate (Zoledronic Acid) therapy in patients with early osteonecrosis of the hip.

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Secondary ID [1]2532170

BONES Study

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Universal Trial Number (UTN)

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Trial acronym

BONES

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Linked study record

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Health condition

Health condition(s) or problem(s) studied:

osteonecrosis of the hip38050

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collapse femoral head38060

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Condition category

Condition code

Musculoskeletal3988398800

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Other muscular and skeletal disorders

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Intervention/exposure

Study type

Interventional

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Description of intervention(s) / exposure

Participants will be randomised to one of two groups, the intervention (zoledronic acid infusion) and control group (placebo infusion). Participants will have a 66% chance of being in the intervention group and a 33% chance of being in the control group. Subjects in the intervention group will be given 5mg Zoledronic acid (via infusion) annually for 3 doses, this means one dose a year for 3 years. Patients with low serum 25OH vitamin D will be supplemented before zoledronate administration.

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Intervention code [1]35260

Treatment: Drugs

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Comparator / control treatment

Subjects in the control group will receive a placebo injection (5mg saline solution) for a similar period.

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Control group

Placebo

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Outcomes

Primary outcome [1]48900

The primary outcome of this project will be the number of patients progressing to stage III or IV on the Association Research Circulation Osseous (ARCO) scale on imaging (Magnetic Resonance Imaging (MRI)) at 12 months and with an X-ray at 36 months, including the number of patients requiring surgical intervention on the affected hip.

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Timepoint [1]48900

Measured at 12 months and 36 months

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Secondary outcome [1]82520

Changes on MRI including: size of lesion and bone oedema, measured at baseline and 12 months.

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Timepoint [1]82520

Measured at baseline and 12 months

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Secondary outcome [2]82530

Disability evaluation, The Harris Hip Score (HHS) evaluated by the Rheumatologist or Orthopaedic surgeon, is a multidimensional observational assessment which contains eight items representing pain, walking function, activities of daily living, and range of motion of the hip joint. Final score ranges from 100 (no disability) to 0 (maximum disability). The HHS is an accepted test as it can detect small changes in hip function

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Timepoint [2]82530

Measured at baseline, 12 months and 36 months

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Secondary outcome [3]82540

Quality of life. Questionnaires will be used to assess quality of life (AQoL and SF36). The AQoL consists of 5 dimensions, each of which has 3 items. The SF-36 is a short-form health survey which yields an 8-scale profile of functional health and well-being scores as well as psychometrically-based physical and mental health summary measures and a preference-based health utility index.

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Timepoint [3]82540

Measured at baseline, 12 months and 36 months

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Secondary outcome [4]82550

Adverse effects. Adverse effects of the treatment zoledronic acid will be obtained through open-ended questions in the questionnaire and confirmed by a checklist. A special focus will include dental side effects. All serious adverse events and pregnancies that arise during the conduct of the trial will be reported by the investigator sponsor to Novartis within 24 hours of awareness, irrespective of causality. Follow-up information related to serious adverse events and pregnancies will also be reported within 24 hours of awareness.

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Timepoint [4]82550

Measured at baseline, 12 months and 36 months

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Secondary outcome [5]82560

Direct health care costs including; visits to a health care providers, prescriptions and over the counter medication, hospitalization and interventions. Data on direct health care costs including; visits to a health care providers, prescriptions and over the counter medication, hospitalization and interventions will be collected using monthly diaries. Participants will be requested to update these diaries and return when participants attend for 12, 24 and 36 monthly follow up. Participants will be required to also include data on indirect costs due to days off work or from usual activities.

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Timepoint [5]82560

3 years

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Eligibility

Key inclusion criteria

symptoms of pain and disability in at least one hip joint and/or positive MRI findings stage I or II on the ARCO classification

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Minimum age

18Years

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Maximum age

80Years

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Gender

Both males and females

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Can healthy volunteers participate?

No

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Key exclusion criteria

Previous hip joint surgery on the affected hip and/or severe pain and disability at rest if treating clinician has recommended surgery and/or Radiographic or MRI findings suggestive for stage III and IV on the ARCO classification

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Study design

Purpose of the study

Treatment

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Allocation to intervention

Randomised controlled trial

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Procedure for enrolling a subject and allocating the treatment (allocation concealment
procedures)

Potential participants who meet the eligibility criteria will be identified by their treating Rheumatologists or Orthopaedic surgeons, followed by a screening assessment conducted by the study research staff. If suitable, participants will be invited to join the study. Prior to treatment, the study research staff will perform a baseline assessment including demographic details, age, sex, duration of symptoms, medical history including prior surgery, trauma and medication use and known risk factors for osteonecrosis. Eligible participants will be allocated their treatment according to a computer-generated table of random numbers created by the study biostatistician to balance for age, sex and 2 stages of MRI severity. Treatments will then be dispensed by participating hospital pharmacies with active and placebo tablets and infusions prepared in identical packaging to maintain blinding.

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Methods used to generate the sequence in which subjects will be randomised (sequence
generation)

computer-generated table of random numbers created by the study biostatistician

Osteonecrosis of the hip is an important cause of musculoskeletal disability and finding therapeutic solutions has proven to be challenging. Osteonecrosis means death of bone which can occur from the loss of the blood supply or some other means. Although any age group may develop osteonecrosis, most patients are between 20 and 50 years old. The most common risk factor is a history of high steroid treatment for some medical condition. The next most common associated condition is a history of high alcohol use. There are some cases of osteonecrosis that occur in patients that are otherwise completely healthy with no detectable risk factors.In the earliest stage of the disease, x-rays appear normal and the diagnosis is made using MRI. The advanced stages of osteonecrosis begin when the dead bone starts to fail mechanically through a process of microfractures of the bone. As the disease progresses, the surace begins to collapse until, finally the integrity of the joint is destroyed. A wide range of surgical treatments with variable success rates have been proposed for the treatment of the osteonecrosis to preserve joint integrity, including core decompression, whereby the venous hypertension that ensues is lessened and revascularisation may be induced leading to bone repair. Nonsurgical treatment options are limited and usually result in a poor prognosis. Early stage disease can be treated with protected weight bearing and physiotherapy, however some studies have shown protected weight bearing to be associated with a greater than 85% rate of femoral head collapse. Unfortunately most studies indicate that the risk for disease progression is greater with nonsurgical treatment than with surgical intervention. There are no esthablished pharmaceuticals for the prevention of treatment of osteonecrosis. Evidence is increasing that the nitrogen containing bisphosphonates may be beneficial in the treatment of osteonecrosis. One bisphosphonates (alendronate) has been evaluated in 60 patients diagnosed with osteonecrosis of the hip. Recent clinical studies have shown very promising results. All patients had symptomatic improvement after one year. Although the follow up time ranged from 3 months to 5 years, only 6 patients progressed to the point of needing surgery.